Crystal structure, Hirshfeld analysis and a mol­ecular docking study of a new inhibitor of the Hepatitis B virus (HBV): ethyl 5-methyl-1,1-dioxo-2-{[5-(pentan-3-yl)-1,2,4-oxa­diazol-3-yl]meth­yl}-2H-1,2,6-thia­diazine-4-carboxyl­ate

Ivachtchenko, A.V.; Kovalenko, S.M.; Kravchenko, D.V.; Mitkin, O.D.; Ivanov, V.V.; Langer, T.

doi:10.1107/S2056989019015986

Crystal structure, Hirshfeld analysis and a molecular docking study of a new inhibitor of the Hepatitis B virus (HBV): ethyl 5-methyl-1,1-dioxo-2-{[5-(pentan-3-yl)-1,2,4-oxadiazol-3-yl]methyl}-2H-1,2,6-thiadiazine-4-carboxylate

A. V. Ivachtchenko, S. M. Kovalenko, D. V. Kravchenko, O. D. Mitkin, V. V. Ivanov and T. Langer

The title compound, a new inhibitor of the Hepatitis B virus (HBV), was prepared via alkylation of 3-(chloromethyl)-5-(pentan-3-yl)-1,2,4-oxadiazole in anhydrous dioxane in the presence of triethylamine.

Keywords: crystal structure; 2H-1,2,6-thiadiazine 1,1-dioxide; hepatitis B; HBV; hydrogen bonding; Hirshfeld surface analysis; molecular docking study.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2056989019015986/su5529sup1.cif Contains datablocks Global, I
	Structure factor file (CIF format) https://doi.org/10.1107/S2056989019015986/su5529Isup2.hkl Contains datablock I
	Chemical Markup Language (CML) file https://doi.org/10.1107/S2056989019015986/su5529Isup3.cml Supplementary material

CCDC reference: 1968398

checkCIF report

Key indicators

Single-crystal X-ray study
T = 293 K
Mean (C-C) = 0.004 Å
R factor = 0.050
wR factor = 0.127
Data-to-parameter ratio = 14.0

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT220_ALERT_2_C Non-Solvent  Resd 1  C   Ueq(max)/Ueq(min) Range        3.2 Ratio
PLAT762_ALERT_1_C CIF Contains no X-Y-H or H-Y-H Angles ..........     Please Check
PLAT906_ALERT_3_C Large K Value in the Analysis of Variance ......      7.824 Check

Alert level G
PLAT005_ALERT_5_G No Embedded Refinement Details Found  in the CIF     Please Do !
PLAT199_ALERT_1_G Reported _cell_measurement_temperature ..... (K)        293 Check
PLAT200_ALERT_1_G Reported   _diffrn_ambient_temperature ..... (K)        293 Check
PLAT395_ALERT_2_G Deviating  X-O-Y    Angle From 120 for O1             106.4 Degree
PLAT909_ALERT_3_G Percentage of I>2sig(I) Data at Theta(Max) Still        52% Note
PLAT910_ALERT_3_G Missing # of FCF Reflection(s) Below Theta(Min).          4 Note
PLAT955_ALERT_1_G Reported (CIF) and Actual (FCF) Lmax Differ by .          1 Units
PLAT961_ALERT_5_G Dataset Contains no Negative Intensities .......     Please Check
PLAT978_ALERT_2_G Number C-C Bonds with Positive Residual Density.          1 Info

   0 ALERT level A = Most likely a serious problem - resolve or explain
   0 ALERT level B = A potentially serious problem, consider carefully
   3 ALERT level C = Check. Ensure it is not caused by an omission or oversight
   9 ALERT level G = General information/check it is not something unexpected

   4 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   3 ALERT type 2 Indicator that the structure model may be wrong or deficient
   3 ALERT type 3 Indicator that the structure quality may be low
   0 ALERT type 4 Improvement, methodology, query or suggestion
   2 ALERT type 5 Informative message, check


checkCIF publication errors

Alert level A
PUBL024_ALERT_1_A The number of authors is greater than 5.
              Please specify the role of each of the co-authors
              for your paper.

   1 ALERT level A = Data missing that is essential or data in wrong format
   0 ALERT level G = General alerts. Data that may be required is missing

Computing details top

Data collection: CrysAlis PRO (Rigaku OD, 2018); cell refinement: CrysAlis PRO (Rigaku OD, 2018); data reduction: CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009) and Mercury (Macrae et al., 2008); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009), SHELXL (Sheldrick, 2015b), PLATON (Spek, 2009) and publCIF (Westrip, 2010).

Ethyl 5-methyl-1,1-dioxo-2-{[5-(pentan-3-yl)-1,2,4-oxadiazol-3-yl]methyl}-2H-1,2,6-thiadiazine-4-carboxylate top

Crystal data top

C₁₅H₂₂N₄O₅S	D_x = 1.341 Mg m⁻³
M_r = 370.42	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, Pbca	Cell parameters from 3271 reflections
a = 12.4962 (5) Å	θ = 3.6–23.3°
b = 9.9237 (4) Å	µ = 0.21 mm⁻¹
c = 29.5925 (15) Å	T = 293 K
V = 3669.7 (3) Å³	Block, colourless
Z = 8	0.4 × 0.2 × 0.1 mm
F(000) = 1568

Data collection top

Rigaku Oxford Diffraction Xcalibur, Sapphire3 diffractometer	3211 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source	2510 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.070
Detector resolution: 16.1827 pixels mm^-1	θ_max = 25.0°, θ_min = 3.0°
ω scans	h = −14→14
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2018)	k = −11→11
T_min = 0.466, T_max = 1.000	l = −25→35
26547 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.050	Hydrogen site location: difference Fourier map
wR(F²) = 0.127	H-atom parameters constrained
S = 1.06	w = 1/[σ²(F_o²) + (0.053P)² + 1.1666P] where P = (F_o² + 2F_c²)/3
3211 reflections	(Δ/σ)_max < 0.001
230 parameters	Δρ_max = 0.24 e Å⁻³
0 restraints	Δρ_min = −0.32 e Å⁻³

Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
S1	0.66349 (5)	0.40561 (6)	0.31677 (2)	0.0462 (2)
O1	0.74895 (14)	0.29562 (18)	0.46836 (6)	0.0577 (5)
O2	0.60666 (16)	0.31342 (17)	0.34444 (7)	0.0646 (6)
O3	0.76374 (15)	0.3626 (2)	0.30037 (8)	0.0726 (6)
O4	0.47430 (16)	0.86020 (18)	0.34934 (7)	0.0668 (6)
O5	0.35185 (14)	0.7296 (2)	0.31536 (7)	0.0654 (6)
N1	0.65072 (15)	0.4628 (2)	0.44365 (7)	0.0472 (5)
N2	0.80748 (16)	0.3561 (2)	0.43291 (8)	0.0514 (5)
N3	0.68614 (14)	0.54419 (19)	0.34784 (7)	0.0415 (5)
N4	0.58953 (16)	0.4585 (2)	0.27686 (7)	0.0495 (5)
C1	0.65689 (19)	0.3647 (2)	0.47179 (9)	0.0463 (6)
C2	0.74512 (17)	0.4525 (2)	0.42013 (8)	0.0402 (5)
C3	0.77420 (18)	0.5405 (2)	0.38103 (9)	0.0467 (6)
H3A	0.788916	0.631017	0.391704	0.056*
H3B	0.838461	0.506142	0.366693	0.056*
C4	0.61014 (18)	0.6400 (2)	0.34937 (8)	0.0427 (6)
H4	0.615584	0.705875	0.371592	0.051*
C5	0.52574 (18)	0.6464 (2)	0.32039 (8)	0.0412 (6)
C6	0.52217 (19)	0.5588 (2)	0.28224 (9)	0.0457 (6)
C7	0.4479 (2)	0.5814 (3)	0.24327 (10)	0.0660 (8)
H7A	0.471161	0.528646	0.217909	0.099*
H7B	0.448204	0.675101	0.235238	0.099*
H7C	0.376781	0.554846	0.251685	0.099*
C8	0.4500 (2)	0.7587 (3)	0.32946 (9)	0.0497 (6)
C9	0.2702 (2)	0.8316 (4)	0.32370 (14)	0.0881 (11)
H9A	0.275933	0.864784	0.354432	0.106*
H9B	0.279751	0.906902	0.303192	0.106*
C10	0.1671 (3)	0.7707 (5)	0.31670 (19)	0.1275 (19)
H10A	0.163950	0.732718	0.286891	0.191*
H10B	0.112282	0.837879	0.319856	0.191*
H10C	0.156092	0.700900	0.338674	0.191*
C11	0.5779 (2)	0.3135 (3)	0.50547 (10)	0.0601 (7)
H11	0.517153	0.375927	0.506023	0.072*
C12	0.5362 (3)	0.1749 (3)	0.49009 (12)	0.0756 (9)
H12A	0.596527	0.113804	0.487578	0.091*
H12B	0.489029	0.139689	0.513284	0.091*
C13	0.4770 (3)	0.1756 (4)	0.44585 (14)	0.0939 (12)
H13A	0.522406	0.211801	0.422662	0.141*
H13B	0.413982	0.230344	0.448575	0.141*
H13C	0.456836	0.085211	0.438077	0.141*
C14	0.6254 (3)	0.3084 (3)	0.55267 (11)	0.0799 (10)
H14A	0.572775	0.269913	0.573035	0.096*
H14B	0.686816	0.248710	0.552328	0.096*
C15	0.6597 (3)	0.4429 (4)	0.57096 (13)	0.1016 (13)
H15A	0.714439	0.480074	0.551891	0.152*
H15B	0.687317	0.431690	0.601003	0.152*
H15C	0.599454	0.502798	0.571657	0.152*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
S1	0.0472 (4)	0.0396 (4)	0.0518 (4)	0.0034 (3)	−0.0079 (3)	0.0008 (3)
O1	0.0566 (11)	0.0612 (11)	0.0553 (12)	0.0133 (9)	0.0089 (9)	0.0161 (9)
O2	0.0825 (14)	0.0438 (10)	0.0674 (13)	−0.0180 (10)	−0.0177 (11)	0.0143 (9)
O3	0.0531 (11)	0.0764 (13)	0.0881 (16)	0.0224 (10)	−0.0045 (11)	−0.0190 (12)
O4	0.0760 (13)	0.0518 (11)	0.0725 (15)	0.0144 (10)	0.0007 (11)	−0.0081 (10)
O5	0.0439 (10)	0.0727 (13)	0.0796 (15)	0.0152 (9)	0.0022 (9)	−0.0008 (10)
N1	0.0432 (11)	0.0428 (11)	0.0555 (14)	0.0035 (9)	0.0051 (10)	0.0075 (10)
N2	0.0458 (11)	0.0587 (13)	0.0497 (14)	0.0063 (10)	0.0053 (10)	0.0090 (10)
N3	0.0394 (10)	0.0387 (11)	0.0463 (12)	−0.0029 (9)	−0.0046 (9)	0.0043 (9)
N4	0.0549 (12)	0.0466 (12)	0.0470 (13)	0.0060 (10)	−0.0082 (10)	−0.0014 (9)
C1	0.0476 (14)	0.0438 (14)	0.0474 (16)	0.0064 (11)	0.0042 (11)	0.0003 (11)
C2	0.0353 (12)	0.0417 (12)	0.0435 (14)	−0.0036 (10)	−0.0049 (10)	−0.0006 (10)
C3	0.0374 (12)	0.0491 (14)	0.0536 (16)	−0.0082 (11)	−0.0061 (11)	0.0061 (12)
C4	0.0438 (13)	0.0377 (12)	0.0466 (15)	−0.0035 (11)	0.0052 (11)	0.0043 (10)
C5	0.0372 (12)	0.0410 (13)	0.0453 (15)	0.0003 (10)	0.0036 (10)	0.0056 (10)
C6	0.0454 (13)	0.0421 (13)	0.0496 (16)	−0.0006 (11)	−0.0025 (11)	0.0073 (11)
C7	0.0763 (19)	0.0634 (17)	0.0583 (19)	0.0160 (15)	−0.0215 (15)	−0.0017 (14)
C8	0.0493 (15)	0.0527 (15)	0.0471 (16)	0.0037 (13)	0.0046 (12)	0.0088 (12)
C9	0.061 (2)	0.103 (3)	0.100 (3)	0.0384 (19)	0.0100 (18)	0.008 (2)
C10	0.0468 (19)	0.139 (4)	0.196 (6)	0.024 (2)	0.007 (2)	0.025 (4)
C11	0.0652 (17)	0.0544 (16)	0.0607 (19)	0.0094 (13)	0.0206 (14)	0.0102 (13)
C12	0.074 (2)	0.0620 (19)	0.091 (3)	−0.0053 (16)	0.0256 (19)	0.0133 (17)
C13	0.083 (2)	0.088 (2)	0.110 (3)	−0.023 (2)	0.007 (2)	−0.003 (2)
C14	0.102 (2)	0.081 (2)	0.056 (2)	0.008 (2)	0.0207 (18)	0.0155 (17)
C15	0.135 (4)	0.099 (3)	0.071 (3)	0.005 (2)	0.001 (2)	−0.009 (2)

Geometric parameters (Å, º) top

S1—O2	1.4183 (19)	C12—C13	1.504 (5)
S1—O3	1.4097 (19)	C14—C15	1.503 (5)
S1—N3	1.678 (2)	C3—H3A	0.9700
S1—N4	1.589 (2)	C3—H3B	0.9700
O1—N2	1.413 (3)	C4—H4	0.9300
O1—C1	1.343 (3)	C7—H7A	0.9600
O4—C8	1.205 (3)	C7—H7B	0.9600
O5—C8	1.327 (3)	C7—H7C	0.9600
O5—C9	1.458 (3)	C9—H9A	0.9700
N1—C1	1.283 (3)	C9—H9B	0.9700
N1—C2	1.373 (3)	C10—H10A	0.9600
N2—C2	1.291 (3)	C10—H10B	0.9600
N3—C3	1.476 (3)	C10—H10C	0.9600
N3—C4	1.344 (3)	C11—H11	0.9800
N4—C6	1.313 (3)	C12—H12A	0.9700
C1—C11	1.492 (4)	C12—H12B	0.9700
C2—C3	1.494 (3)	C13—H13A	0.9600
C4—C5	1.361 (3)	C13—H13B	0.9600
C5—C6	1.425 (3)	C13—H13C	0.9600
C5—C8	1.487 (3)	C14—H14A	0.9700
C6—C7	1.497 (3)	C14—H14B	0.9700
C9—C10	1.439 (5)	C15—H15A	0.9600
C11—C12	1.539 (4)	C15—H15B	0.9600
C11—C14	1.518 (4)	C15—H15C	0.9600

O2—S1—N3	107.26 (11)	N2—C2—C3	120.9 (2)
O2—S1—N4	110.56 (11)	N3—C3—C2	110.41 (18)
O3—S1—O2	116.64 (13)	N3—C4—C5	124.0 (2)
O3—S1—N3	106.67 (11)	C4—C5—C6	119.7 (2)
O3—S1—N4	111.17 (13)	C4—C5—C8	114.5 (2)
N4—S1—N3	103.55 (10)	C6—C5—C8	125.5 (2)
C1—O1—N2	106.41 (17)	N4—C6—C5	122.6 (2)
C8—O5—C9	116.2 (2)	N4—C6—C7	114.7 (2)
C1—N1—C2	102.8 (2)	C5—C6—C7	122.6 (2)
C2—N2—O1	102.71 (18)	O4—C8—O5	124.6 (2)
C3—N3—S1	118.03 (15)	O4—C8—C5	123.6 (2)
C4—N3—S1	118.60 (16)	O5—C8—C5	111.6 (2)
C4—N3—C3	121.5 (2)	C10—C9—O5	108.1 (3)
C6—N4—S1	122.23 (18)	C1—C11—C12	109.3 (2)
O1—C1—C11	116.3 (2)	C1—C11—C14	111.5 (2)
N1—C1—O1	112.9 (2)	C14—C11—C12	112.0 (3)
N1—C1—C11	130.7 (2)	C13—C12—C11	114.8 (3)
N1—C2—C3	123.9 (2)	C15—C14—C11	114.4 (3)
N2—C2—N1	115.1 (2)

S1—N3—C3—C2	−71.7 (2)	N4—S1—N3—C4	31.0 (2)
S1—N3—C4—C5	−14.3 (3)	C1—O1—N2—C2	0.6 (3)
S1—N4—C6—C5	13.9 (3)	C1—N1—C2—N2	−0.9 (3)
S1—N4—C6—C7	−171.32 (19)	C1—N1—C2—C3	176.3 (2)
O1—N2—C2—N1	0.2 (3)	C1—C11—C12—C13	−62.4 (3)
O1—N2—C2—C3	−177.1 (2)	C1—C11—C14—C15	61.6 (4)
O1—C1—C11—C12	−66.6 (3)	C2—N1—C1—O1	1.4 (3)
O1—C1—C11—C14	57.8 (3)	C2—N1—C1—C11	−175.8 (3)
O2—S1—N3—C3	78.61 (19)	C3—N3—C4—C5	−178.3 (2)
O2—S1—N3—C4	−85.95 (19)	C4—N3—C3—C2	92.4 (3)
O2—S1—N4—C6	83.5 (2)	C4—C5—C6—N4	9.6 (4)
O3—S1—N3—C3	−47.1 (2)	C4—C5—C6—C7	−164.7 (2)
O3—S1—N3—C4	148.37 (19)	C4—C5—C8—O4	23.7 (4)
O3—S1—N4—C6	−145.3 (2)	C4—C5—C8—O5	−152.6 (2)
N1—C1—C11—C12	110.4 (3)	C6—C5—C8—O4	−149.2 (3)
N1—C1—C11—C14	−125.2 (3)	C6—C5—C8—O5	34.4 (3)
N1—C2—C3—N3	−50.0 (3)	C8—O5—C9—C10	−166.0 (3)
N2—O1—C1—N1	−1.3 (3)	C8—C5—C6—N4	−177.8 (2)
N2—O1—C1—C11	176.3 (2)	C8—C5—C6—C7	7.9 (4)
N2—C2—C3—N3	127.1 (2)	C9—O5—C8—O4	2.1 (4)
N3—S1—N4—C6	−31.1 (2)	C9—O5—C8—C5	178.4 (2)
N3—C4—C5—C6	−8.5 (4)	C12—C11—C14—C15	−175.5 (3)
N3—C4—C5—C8	178.1 (2)	C14—C11—C12—C13	173.4 (3)
N4—S1—N3—C3	−164.45 (17)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C4—H4···N2ⁱ	0.93	2.54	3.431 (3)	161

Symmetry code: (i) −x+3/2, y+1/2, z.

Short contacts (Å) in the crystal of compound 3 top

Atom1···Atom2	Length	Length - vdW
S1..H7Bⁱ	3.090	0.090
O2···H7Bⁱ	2.813	0.093
H7A···O4ⁱ	2.687	-0.033
H12B···N2ⁱⁱ	2.772	0.022
O4···H14Aⁱⁱⁱ	2.700	-0.020
C8···H14Aⁱⁱⁱ	2.913	0.013
C6···H10B^iv	2.978	0.078
O2···C3^v	3.275	0.055
O2···H3A^v	2.634	-0.086
O3···C4^v	3.077	-0.143
N2···H3A^v	2.816	0.066
N2···HA^v	2.538	-0.212
H3B···O4^v	2.799	0.079

Symmetry codes: (i) -x + 1, y - 1/2, -z + 1/2; (ii) x - 1/2, -y + 1/2, -z + 1; (iii) -x + 1, -y + 1, -z + 1; (iv) -x + 1/2, y - 1/2, z; (v) -x + 3/2, y - 1/2, z.

Binding affinity parameters of title molecule with HBV core proteins top

PDB refcode	Est. binding energy (kcal mol^-1)	Binding affinity score
5E0I	-14.54	-25.2
5GMZ	-14.30	-14.99
5WRE	-16.03	-8.28
5T2P	-17.05	-22.34

Torsion angles (°) comparison for X-ray, ab initio and docking data top

Torsion angle	X-ray	M062x/cc-pVDZ	5E0I	5GMZ	5WRE	5T2P
O2—S1—N4—C6	83.5 (2)	78.7	93.13	93.2	93.1	137.4
C5—C8—O5—C9	178.4 (2)	178.9	-112.9	-79.3	-110.4	-163.1
S1—N3—C3—C2	-71.7 (2)	-71.5	-148.5	-126.7	-172.5	-80
O1—C1—C11—C14	57.8 (3)	49.9	50.1	-112.9	9.8	52.8

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Crystal structure, Hirshfeld analysis and a mol­ecular docking study of a new inhibitor of the Hepatitis B virus (HBV): ethyl 5-methyl-1,1-dioxo-2-{[5-(pentan-3-yl)-1,2,4-oxa­diazol-3-yl]meth­yl}-2H-1,2,6-thia­diazine-4-carboxyl­ate

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Crystal structure, Hirshfeld analysis and a molecular docking study of a new inhibitor of the Hepatitis B virus (HBV): ethyl 5-methyl-1,1-dioxo-2-{[5-(pentan-3-yl)-1,2,4-oxadiazol-3-yl]methyl}-2H-1,2,6-thiadiazine-4-carboxylate